Bone cells respond in specific ways to various hormones and growth factors, but the biology of skeletal innervation and its physiologic significance in bone metabolism is poorly understood. With the introduction of immunohistochemical staining techniques and new molecular biology tools, the knowledge in this field has significantly improved. In this review, we update current understanding of the effects of neuropeptides on bone metabolism, specifically vasoactive intestinal peptide (VIP) and calcitonin-gene related peptide (CGRP). In addition, new information concerning the role of growth factors, such as neurotrophins, is also discussed. There is strong evidence to suggest that bone can be a target of the nervous system. Further investigations in this field will allow us to answer questions related to pre-natal development, bone growth, fracture healing, osteoporosis, osteoarthritis or neoplasias of mesoderm origin.